The genetic link between immunity and schizophrenia
For many diseases, genome-wide association studies (GWAS) have identified genetic variants in loci close to immune-related genes, underscoring the importance of the immune system in the pathophysiology of many diseases. With respect to schizophrenia, emerging evidence suggests that inflammation in the central nervous system may be an underlying factor with monocytes and microglia playing a central role.
Identifying genetic variants of immune-related genes
Given the central role of inflammation in many diseases, the IMAGENE project elucidated the link of immune genetic variants with schizophrenia. “We looked into genetic factors that affect variation in immune response among different individuals and found that some of them help us to better understand complex diseases such as schizophrenia,” explains Marie Skłodowska-Curie Actions (MSCA) research fellow Sarah Kim-Hellmuth. The research was undertaken with the support of the MSCA programme and involved the comparison of expression quantitative trait loci (eQTLs) – genetic variants associated with gene expression – in monocytes at baseline and upon immune stimulation. This led to the identification of so-called response eQTLs (reQTLs), where the eQTL effect differs between immune stimuli. “Such genetic variants can impact the response to infection, and highlight the context-specificity of genetic regulation,” says Kim-Hellmuth. Interestingly, results demonstrated that genetic polymorphisms associated with schizophrenia risk are eQTLs of immune response genes. These results indicate that environmental interactions with microbial ligands might play a role in the underlying mechanism of genetic risk of schizophrenia. Extensive efforts also went into the development of a method for studying the cell specificity of eQTLs in bulk tissue by mapping interactions between computational estimates of neuron abundance and genotype in 13 different brain tissues of post-mortem donors from the Genotype-Tissue Expression (GTEx) database. Applying this approach to the massive GTEx resource enabled the research fellow to identify the cellular origin of hundreds of disease susceptibility loci including those for psychiatric disorders.
The importance of studying variability in immune response
Emerging evidence underscores the importance of the human immune system not only in host protection and autoimmune and inflammatory diseases, but also in cancer, metabolism and ageing. Given this central role in many human pathologies, it is crucial to understand the variability of immune responses at the population level and how this variability relates to disease susceptibility. Studying the genetic influence on immune response is impeded by the complexity of the immune system. This pervasive network consists of many different cell types that respond to a plethora of signals, interact with each other, and induce different effector functions under diverse kinetics. “IMAGENE results illustrate the importance of studying genetic variation in the right cell type and under relevant conditions to resolve functional genetic variants and the transcriptional responses associated with schizophrenia,” concludes Kim-Hellmuth. Furthermore, the IMAGENE project supports a model where the genetic risk of a disease can sometimes be driven by the failure to respond properly to an environmental stimulus. This realisation opens new avenues for tailored treatments in individuals suffering from schizophrenia.
Keywords
IMAGENE, schizophrenia, eQTL, immune response, genetic variants, monocytes, genetic risk, microglia, cell specificity, expression quantitative trait loci
